Clinical consequences of aspirin and clopidogrel resistance: an overview.

The aim of this review is to introduce the concept of personalized medicine in secondary stroke prevention with antiplatelet medication. In the last years, many studies have been conducted regarding aspirin resistance and genotyping of clopidogrel metabolism. A review of the currently published data on this issue emphasizes the importance of focusing on the individualizing approach in antiplatelet therapy to achieve maximal therapeutic beneficial effect. However, many authors suggest that, before new information from ongoing trials become available, good clinical practice should dictate the use of low dose of aspirin that was shown to be effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, because higher doses do not have significantly better efficacy than lower doses in secondary stroke prevention, but lower-dose aspirin is associated with less side effects. On the other hand, many factors are associated with clopidogrel resistance, and recent genetic studies showed that the CYP2C19*2 genotype (loss-of-function allele) is related to poor metabolism of clopidogrel, but larger studies are needed to definitively confirm or rule out the clinical significance of this genetic effect. The aim of personalized approach in secondary stroke prevention is to take the most appropriate medicine in the right dose in accordance with the clinical condition of the patient and associated risk factors.

Three-dimensional multivoxel spectroscopy of the healthy hippocampus-are the metabolic differences related to the location?

AIM: The aim of this study was to determine the bilateral distribution of proton metabolites along the long axis of the hippocampus. MATERIALS AND METHODS: Forty-one healthy volunteers were examined using a 1.5T magnetic resonance imaging system, using proton three-dimensional spectroscopic imaging (3D CSI) of the left and the right hippocampus separately. Three dominant signals were measured: choline (Cho), total creatine (tCr), and n-acetylaspartate (NAA) and expressed as ratios of Cho:tCr, NAA:tCr, NAA:Cho and NAA:(Cho+tCr). We compared the data from three hippocampal regions: head, body and tail. RESULTS: Lower NAA:tCr ratios were found in head compared with the body (p<0.05) and in the head compared with the tail (p<0.05) bilaterally. Lower NAA:Cho and NAA:(Cho+tCr) ratios were found in the head compared with the body (p<0.05), in the body compared with the tail (p<0.05), and in the head compared with the tail (p<0.05) bilaterally. There was no statistically significant difference between the left and the right hippocampus. CONCLUSION: Ratios of NAA:tCr, NAA:Cho, and NAA:(Cho+tCr) in hippocampal tissue were significantly higher posteriorly than anteriorly. As the differences are present in healthy volunteers, the appearance in patients related to approximate voxel positioning within hippocampi may result in false-positive results.

Symmetry of post-movement beta-ERS and motor recovery from stroke: a low-resolution EEG pilot study.

The inter-hemispheric symmetry of electroencephalographic (EEG) post-movement beta-event-related synchronization (PMBS) after movements on a drawing board was studied in eight acute stroke subjects with mild hemiparesis and eight normal subjects. A follow-up testing was conducted 3 months after the initial recordings with a twofold purpose: (1) to validate the reproducibility of the experimental protocol in normal subjects; and (2) to study changes of inter-hemispheric PMBS-symmetry as a response to recovery of motor function. PMBS values were calculated and their topographic distributions illustrated at various time instances following movement offset. Significant PMBS patterns were present in all normal subjects, with only minor differences within consecutive recordings. The side of hemiparesis in acute stroke subjects could be distinguished (P = 0.04) on the basis of the signed symmetry index, a quantitative measure of lateralization. The follow-up testing on three recovered stroke subjects revealed a trend of changes in the lateralization towards the contralateral side of movement, an indication that the cortical organization of movement following recovery turned out as reported for normal subjects. Further clinical investigations need to be carried out to evaluate the relationship between recovery and PMBS symmetry on a large number of subjects, using the method presented here.

Depression in Parkinson's disease: an EEG frequency analysis study.

Although depression is a common finding in Parkinson's disease (PD), its neurobiological mechanism is still unknown. The purpose of this study was to determine whether there are specific spectral electroencephalographic (EEG) characteristics that distinguish depressed from non-depressed PD patients. The study was performed in 24 patients with idiopathic PD whose antiparkinson medication was stopped 24h beforehand. They were divided into two groups of 12 patients each, one with depressive symptomatology, and one without. The groups did not differ with respect to age, sex distribution, and disease severity and duration. All recordings were conducted using a 16-channel electroencephalograph, and artifact-free EEG was processed using a Fast Fourier Transformation. The EEG of depressed PD patients showed significantly less absolute and relative power in spectral band 7.5-10Hz (alpha1), and slightly more relative power in spectral band 10.513Hz (alpha2), while there was no difference in other spectral bands. Topographic analysis of the alpha1 absolute power revealed that, while in non-depressed patients this activity has a clear occipital maximum (and thus corresponds to the standard background activity), in depressed patients its maximum was shifted anteriorally toward the parietal region. Topographic analysis of the significance of the difference between the groups in the relative power of alpha1 and alpha2 bands revealed opposite gradients, posterior to anterior and anterior to posterior directions, respectively. The spectral EEG characteristics of the depressed PD patients not only differed from the spectral EEG characteristics of non-depressed PD patients, but they were also different from the usually reported spectral EEG characteristics of depressed patients without neurological disease. We propose that our data are sufficient to raise the possibility for the existence of a distinctive neurobiological substrate of depression in PD. This is not just a simple addition of two neurobiological substrata, one of depression (as it is determined in non-neurological patients) and one of PD, but rather a complex product of their interaction.

Correlation between Bereitschaftspotential and reaction time measurements in patients with Parkinson's disease. Measuring the impaired supplementary motor area function?

For a long time, reaction time (RT) testing has been used for objective assessment of characteristics of the movement impairments in patients with Parkinson's disease (PD). On the other hand, it is supposed that Bereitschaftspotential (BP) reflects CNS preparatory activity for the execution of voluntary movements, and amplitudes of BP are generally smaller in PD. In order to analyze possible correlations between two methods, we studied 15 drug-naive patients with idiopathic PD (Hoehn and Yahr stage from 1 to 2.5). BP was recorded from three scalp locations: Cz, C3, and C4, and Lateralized Potential (LP) was additionally calculated as a C3-C4 difference waveform. We recorded amplitudes of the initial part of BP (at 650 ms before movement-NS1), the maximal amplitude immediately before movement onset (N1), and the N1-NS1 difference (NS2), from the Cz and LP recordings. Two RT testing paradigms were used: Simple Reaction Time (SRT) and Choice Reaction Time (ChRT). The only significant correlation between RT parameters and BP amplitudes from Cz was negative correlation between dT (difference time between Choice Reaction Time and Simple Reaction Time), on one hand, and NS1 (P = 0.006) and N1 (P = 0.026), on the other. However, Cz-NS2 did not correlate with any of the RT parameters. Our data suggest that PD patients with smaller difference between ChRT and SRT, that is presumably caused by the lesser capacity of the movement pre-programming, have smaller (i.e., less negative) BP amplitudes. This association is especially pronounced for the earlier, NS1 amplitude that is supposed to reflect the activity of the supplementary motor area (SMA). The diminished capacity of SMA activation may be the cause of the both, smaller early BP amplitudes, and smaller ChRT-SRT difference, in PD patients.

[Delayed-onset dystonia due to asphyxia in the perinatal period]. / Distonija odlozenog pocetka izazvana asfiksijom u perinatalnom vremenu.

The phenomenon of delayed-onset dystonia following presumed "static" brain injuries was described after stroke and head trauma. Burke et al. described a different category of secondary dystonia, where perinatal injury (asphyxia) caused minimal or no immediate neurological deficit, with the delay of years before dystonia emerged. This type of dystonia following perinatal injury has been termed "delayed onset dystonia due to static encephalopathy of childhood". According to the definition of dystonia, we were able to select 5 patients with the aetiologic diagnosis of perinatal asphyxia from the group of 347 out- and inpatients (1.4%) treated for various types of dystonia at the Movement Disorders Department (Institute of Neurology, CCS, Belgrade) from November 1986 to November 1994. At onset of dystonia the mean age of patients was 13.2 years (range from 10 to 17), with combined initial involvement of the arm and neck in 3 patients. The period from the onset of the disease to the maximum severity lasted 8.2 years (range from 4 to 14), resulting in segmental brachial dystonia in 3, hemidystonia and generalized dystonia in one patient each (Table 1). The adverse perinatal events are described in Table 2. Three of our patients had delayed achievements of developmental milestones. All patients were regularly schooled and had preserved intellectual capacities, except the patient 3 whose achievements were below average (IQ = 86). Different drugs were administered (Table 3), but moderate effects were achieved only with trihexyphenidyl in two patients (daily doses of 24 mg and 30 mg, respectively), and baclofen (80 mg p.d.) in one patient. In this study we describe 5 new patients who fulfilled the criteria for the diagnosis of delayed-onset dystonia due to perinatal asphyxia (Tables 1 and 2). We accepted the approach of Saint-Hilaire et al. to suggest a relationship between perinatal asphyxia and later occurrence of dystonia in our 5 patients. However, coincident occurrence of a primary dystonia with a static encephalopathy of childhood due to perinatal asphyxia cannot be excluded. This phenomenon of delayed appearance of dystonia was also described in other forms of static cerebral injury; i.e. stroke, head trauma or anoxic brain damage. Interestingly enough, age at the time of anoxia or brain insults seemed to be crucial for the development of dystonia: those who suffer acute brain insults during childhood or early life are more likely to develop dystonia than the older patients. Therefore, the "static" nature of encephalopathy induced by perinatal asphyxia is questionable. Finally, this study strengthens the suggestion that perinatal asphyxia can lead to delayed-onset dystonia, and, since "some of these patients closely resemble cases of idiopathic torsion dystonia, the prior occurrence of asphyxia should be used as a criterion of exclusion for that diagnosis".

Local treatment of spasmodic torticollis with botulinum toxin.

Fifteen patients with spasmodic torticollis were treated with local injections of botulinum--A toxin. All the patients were followed for a period of 4 to 7 months. Thirteen out of 15 patients (86%) improved in the amount of sustained movements of torticollis. In six out of 9 patients presenting with pain complete relief was noted. Beneficial effects of botulinum toxin injections lasted from 2 to 3 months, with reproducible efficacy after repeated injections. The most frequent side effect was dysphagia, presented in 10 patients.

Open study of sustained-release formulation of levodopa and benserazide in parkinsonian patients.

The efficacy of a novel oral sustained-release preparation of levodopa/benserazide (Madopar HBS) was compared to that of previous conventional levodopa/benserazide treatment in 15 patients with idiopathic Parkinson's disease and with severe fluctuations in motor response to long-term levodopa therapy. In ten patients who suffered from clear-cut "end-of-dose" deterioration, significant benefit was obtained on HBS form, while 5 patients did not respond well to the new levodopa preparation. Plasma levels of levodopa were more stable with HBS compared to conventional levodopa preparation in our patients, although doses of HBS form required for an optimal response averaged 1.48 times that of previous conventional levodopa.

Dexamethasone suppression test in patients with Parkinson's disease.

The Dexamethasone Suppression Test (DST), supposed to effectively distinguish between endogenous and nonendogenous depression, was performed in a group of 34 patients with Parkinson's disease. Abnormal DST results were observed in 50% of the patients. The patients were clinically divided into subgroups of depressed and nondepressed parkinsonians. Abnormal DST results were significantly more frequent in depressed (75%) than in nondepressed parkinsonians (27.7%).

Reduced rapid eye movement sleep latency in patients with Parkinson's disease.

Rapid eye movement (REM) sleep latency (time from sleep onset to the first REM episode) was measured in 39 patients with idiopathic Parkinson's disease. Reduced REM sleep latency (less than or equal to 65.0 min) was found in a high proportion of patients (69%). Since reduced REM sleep latency may be a trait-like abnormality relatively specific to primary depression, we evaluated this parameter in two groups of parkinsonian patients: depressed (16 patients) and non-depressed (23 patients). Its incidence was significantly higher in depressed patients with Parkinson's disease.

[Clinical characteristics of progressive supranuclear paralysis (the Steele-Richardson-Olszewski syndrome)]. / Klinicke karakteristike progresivne supranuklearne paralize (sindrom Steele-Richardson-Olszewskog).

We analyzed the clinical features and therapeutic response of 6 patients with progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). The mean duration from the onset to establishing the diagnosis was 2.7 years, with the initial false diagnosis of Parkinson's disease in 4 patients. The most common symptoms at the moment of diagnosing were unsteady gait, speech difficulties, forgetfulness and rigidity, in addition to impairment of vertical gaze. In all the patients therapeutical response was inadequate. Clinical criteria for differential diagnosis of progressive supranuclear palsy are discussed.

Depression and Parkinson's disease: possible role of serotonergic mechanisms.

Depression is frequently encountered in Parkinson's disease and was seen to occur in 14 of 26 patients studied. The levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin (5-HT), in CSF samples of the patients were significantly lower than in those of controls. However, within the group of patients the levels of 5-HIAA in CSF samples were significantly lower in the depressive subgroup compared with the non-depressive patients. Moreover, no correlation was recorded between motor disability and depression. The results indicate that disturbed 5-HT metabolism may possibly play a role in Parkinson's disease as a predisposing factor in the development of depression.

Cyclic nucleotides in cerebrospinal fluid of drug-free Parkinson patients.

Concentrations of cyclic nucleotides--adenosine-3',5'-monophosphate (c-AMP) and guanosine-3',5'-monophosphate (c-GMP)--were measured in cerebrospinal fluid (CSF) of 17 drug-free Parkinson patients and 12 controls. No significant difference between the cyclic nucleotide contents (p greater than 0.05) in CSF of patients and controls was detected, nor was there a correlation between the content and the degree of neurological disability. Besides, no changes in the cyclic nucleotide contents were detected in the subgroups of patients according to the prominence of tremor or rigidity/akinesia as the main symptoms of the disease.